Abstract
Lymphangioleiomyomatosis (LAM) is a rare and progressive systemic disease affecting mainly young women of childbearing age. A deterioration in lung function is driven by neoplastic growth of atypical smooth muscle-like LAM cells in the pulmonary interstitial space that leads to cystic lung destruction and spontaneous pneumothoraces. Therapeutic options for preventing disease progression are limited and often end with lung transplantation temporarily delaying an inevitable decline. To identify new therapeutic strategies for this crippling orphan disease, we have performed array based and metabolic molecular analysis on patient-derived cell lines. Our results point to the conclusion that mitochondrial biogenesis and mitochondrial dysfunction in LAM cells provide a novel target for treatment.
Highlights
Supplementary information The online version of this article contains supplementary material, which is available to authorized users.Ten-year survival of the progressive and systemic orphan disease, Lymphangioleiomyomatosis (LAM) (1–9/ 1,000,000 adult women) [1], ranges from 40% to 79% [2], but these figures do not fully capture the significant and debilitating reduction in life-quality experienced by most sufferers
Through a combination of techniques, we have identified gene expression profiles and miRNA signatures that strongly indicate that an alteration in mitochondrial biogenesis and function are among the key determinants behind increased VEGF production and accelerated cell proliferation
PPARGC1B overexpression is linked to increased mitochondrial number [13, 14], the active PRG isoform 4 to increased mitochondrial membrane potential and cellular respiration [13, 14], while estrogen-related receptor gamma (ESRRG) to control of mitochondrial biogenesis and energy metabolism [6, 14]
Summary
While a number of organs can be affected, including the kidney and associated lymph nodes, it is the deterioration in lung function, which leads to disease progression. The early disease symptoms of LAM show high similarity to asthma, chronic obstructive pulmonary disease, and other obstructive lung diseases; the condition is frequently misdiagnosed [3]. Through a combination of computer tomography, serological testing of increased serum vascular endothelial growth factor-D (VEGFD), and matrix metalloproteinase (MMP) levels, and lung biopsy, can clinicians confirm a LAM diagnosis with confidence [4]. The progression of the disease is relatively slow, most patients suffer from accelerating respiratory failure and can experience decades long dyspnea before lung transplantation is considered as a “last-resort” therapy
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